Hydroxydiclofenac glucuronide

Figure 5 Metabolism of diclofenac in humans.

diclofenac acylglucuronide in hepatocytes may be an important step in the production of antigenic covalent drug-protein adducts.

The pattern and magnitude of the immune response to drug-protein adducts is likely to vary between individuals, potentially explaining differences in susceptibility to hepato-toxicity. A major determinant of interindividual variation in immune reactions is likely to be interindividual variation in the production of immunoregulatory cytokines, such as interleukin-10 (IL-10) and -4 (IL-4), both of which are encoded by polymorphic genes. A small case-control study has shown an association between diclofenac-hepatotoxicity and the -627*A allele in the IL-10 gene (which reduces transcription) and -590T allele in the IL-4 gene, which increases transcription (145). Low IL-10 and high IL-4 levels would favor a Th-2-mediated antibody response to neoantigenic stimulation and hence could be associated with disease susceptibility. The risk of hepatotoxicity was increased by fivefold in subjects carrying variant alleles for both the IL-10 and IL-4 genes (145).

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